Acquired immunodeficiency syndrome (AIDS), the global epidemic disease caused by HIV-1, has created an urgent need for new classes of antiviral agents (UNAIDS/World Health Organization (2003) AIDS Epidemic Update (UNAIDS—World Health Organization, Geneva)). The envelope glycoprotein of HIV-1 is a trimer consisting of three gp120 exterior envelope glycoproteins and gp41 transmembrane glycoproteins (Chan et al. Cell 1997, 89, 263-273; Wyatt et al. Science 1998, 280, 1884-1888; Tan et al. Proc. Natl. Acad. Sci. USA 1997, 94, 12303-12308). Viral infection is initiated by gp120 binding to CD4 on the host cell surface (Klatzmann et al. Nature 1984, 312, 767-768; Dalgleish et al. Nature 1984, 312, 763-767). The binding of these two proteins promotes a conformational change in gp120 that increases its affinity with a second host cell receptor, one of the chemokine receptors, CCR5 and CXCR4 (Trkola et al. Nature 1996, 384, 184-187; Feng et al. Science 1996, 872-877; Doranz et al. Cell 1996, 85, 1149-1158; Dragic et al. Nature 1996, 381, 667-673; Wu et al. Nature 1996, 384, 179-183). The interaction of gp120 with its receptors is thought to promote further conformational rearrangements in HIV-1 envelope that drive fusion of the viral and host cell membranes. Blocking of these interactions between gp120 and cell surface receptors is an attractive goal for preventing HIV-infection.
A 12-residue peptide [RINNPWSEAMM (SEQ ID NO:1)] was discovered by phage library (Ferrer et al. J. Virol. 1999, 73, 5795-5802). Its mode of action showed (Biorn et al. Biochemistry 2004, 43, 1928-1938) that, the peptide inhibited the interaction of gp120 to CD4 and 17b, an antibody that recognizes an epitope overlapping the CCR5 binding site, with micromolar affinity. The various mutations and truncations of the peptide confirmed that the entire sequence with the large aromatic residue Trp next to Pro is critical for binding.